Reduction of mortality, cardiac damage, and cerebral damage by IL-1 inhibition in a murine model of TTP.

ABSTRACT: Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in von Willebrand factor cleavage resulting in capillary microthrombus formation and ischemic organ damage. Interleukin-1 (IL-1) has been shown to drive sterile inflammation after ischemia and could play an essential contribution to postischemic organ damage in TTP. Our objectives were to evaluate IL-1 involvement during TTP and to test the efficacy of the recombinant IL-1 receptor antagonist, anakinra, in a murine TTP model. We retrospectively measured plasma IL-1 concentrations in patients with TTP and controls. Patients with TTP exhibited elevated plasma IL-1α and -1ß concentrations, which correlated with disease course and survival. In a mouse model of TTP, we administered anakinra (IL-1 inhibitor) or placebo for 5 days and evaluated the efficacy of this treatment. Anakinra significantly reduced mortality of mice (P < .001). Anakinra significantly decreased TTP-induced cardiac damage as assessed by blood troponin concentrations, evaluation of left ventricular function by echocardiography, [18F]fluorodeoxyglucose positron emission tomography of myocardial glucose metabolism, and cardiac histology. Anakinra also significantly reduced brain TTP-induced damage evaluated through blood PS100b concentrations, nuclear imaging, and histology. We finally showed that IL-1α and -1ß trigger endothelial degranulation in vitro, leading to the release of von Willebrand factor. In conclusion, anakinra significantly reduced TTP mortality in a preclinical model of the disease by inhibiting both endothelial degranulation and postischemic inflammation, supporting further evaluations in humans.

Thoracic manifestations of IgG4-related disease.

Immunoglobulin G4-related disease (IgG4-RD) is a recently described rare systemic fibroinflammatory disease with an estimated incidence of less than 1 in 100,000 persons per year. The disease can affect virtually any organ and is characterized by unifying histopathological findings. Recently, four subgroups of patients have been characterized: hepatobiliary, head and neck, Mikulicz syndrome and retroperitoneal fibrosis, who illustrate the mainly abdominal and ENT tropism of the disease. Yet, thoracic involvement is not uncommon. It can be detected in up to 30% of patients with systemic IgG4-RD and is the exclusive manifestation of the disease in about 10% of cases. Clinical symptoms are nonspecific and may include dyspnoea, cough or chest pain. Chest CT findings are heterogeneous and primarily include peribronchovascular thickening, nodules, ground-glass opacities and lymphadenopathy. There is no specific diagnostic test for IgG4-RD thoracic involvement, which may mimic malignancy or vasculitis. Therefore, a cautious approach is needed to make an accurate diagnosis: a search for extra-thoracic manifestations, elevated serum IgG4 levels, circulating levels of plasmablasts and pathologic evidence of disease is warranted. Although very suggestive, neither the presence of a polyclonal IgG4 lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis are sufficient to confirm the histological diagnosis. Steroids are recommended as first-line therapy. Rituximab or disease-modifying antirheumatic drugs may be used in relapsed or rare cases of steroid-refractory disease. In this review, we summarize current knowledge regarding the pathophysiology, epidemiology, diagnostic modalities (clinical-biological-imaging-histopathology) and treatment of IgG4-RD thoracic involvement.

Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factors, prognostic and screening possibilities.

Chloroquine (CQ) and its hydroxylated analog, hydroxychloroquine (HCQ), are 4-aminoquinoline initially used as an antimalarial treatment. CQ and HCQ (4-aminoquinoline, 4-AQ) are today used in rheumatology, especially to treat rheumatoid arthritis and systemic lupus erythematosus. Their mechanism of action revolves around a singular triptych: 4-AQ acts as alkalizing agents, ionized amphiphilic molecules, and by binding to numerous targets. 4-AQ have so pleiotropic and original mechanisms of action, providing them an effect at the heart of the regulation of several physiological functions. However, this broad spectrum of action is also at the origin of various and original side effects, notably a remarkable chronic systemic toxicity. We describe here the 4-AQ-induced lesions on the eye, the heart, muscle, the nerves, the inner ear, and the kidney. We also describe their prevalence, their pathophysiological mechanisms, their risk factors, their potential severity, and the means to detect them early. Most of these side effects are reversible if treatment is stopped promptly. This 4-AQ-induced toxicity must be known to prescribing physicians, to closely monitor its appearance and stop treatment in time if necessary.

Remote optimization of an ultracold atoms experiment by experts and citizen scientists.

We introduce a remote interface to control and optimize the experimental production of Bose-Einstein condensates (BECs) and find improved solutions using two distinct implementations. First, a team of theoreticians used a remote version of their dressed chopped random basis optimization algorithm (RedCRAB), and second, a gamified interface allowed 600 citizen scientists from around the world to participate in real-time optimization. Quantitative studies of player search behavior demonstrated that they collectively engage in a combination of local and global searches. This form of multiagent adaptive search prevents premature convergence by the explorative behavior of low-performing players while high-performing players locally refine their solutions. In addition, many successful citizen science games have relied on a problem representation that directly engaged the visual or experiential intuition of the players. Here we demonstrate that citizen scientists can also be successful in an entirely abstract problem visualization. This is encouraging because a much wider range of challenges could potentially be opened to gamification in the future.

Vascular endothelial-cadherin is involved in endothelial cell detachment during thrombotic thrombocytopenic purpura.

BACKGROUND: Immune thrombotic thrombocytopenic purpura (i-TTP) is a life-threatening thrombotic microangiopathy linked to ADAMTS-13 deficiency. It has long been assumed that the activation of endothelial cells is the triggering factor for the thrombotic thrombocytopenic purpura crisis. Circulating endothelial cells (CECs) have been shown to be a biomarker of vascular damage and are associated with the clinical severity of i-TTP. However, the mechanisms leading to endothelial cell detachment remain unclear. OBJECTIVES: We investigated junctional destabilization the mechanisms underlying cell detachment in thrombotic thrombocytopenic purpura. METHODS: We quantified CECs in i-TTP patients and investigated the effect of plasmas in vitro by measuring phosphorylation and internalization of vascular endothelial (VE)-Cadherin and in vivo in a vascular permeability model. RESULTS: In plasma from i-TTP patients, we show that CEC count is associated with severity and correlated to intracellular calcium influx (P < .01). In vitro, serum from i-TTP patients induced stronger detachment of human umbilical vein endothelial cells than serum from control patients (P < .001). Plasma from i-TTP patients induced a higher calcium-dependent phosphorylation (P < .05) and internalization (P < .05) of VE-cadherin compared with plasma from control patients. This effect could be reproduced by immunoglobulin (Ig)G fraction isolated from patient plasma and, in particular, by the F(ab)'2 fragments of the corresponding IgG. In addition, subcutaneous injection of i-TTP plasma into mice resulted in higher vascular permeability than plasma from control patients. An inhibitor of endothelial calcium influx, ITF1697, normalized this increase in permeability. CONCLUSION: Our results suggest that plasma-induced endothelial activation also leads to an increase in vascular permeability. They contribute to the understanding of the mechanisms behind the presence of elevated CECs in patients' blood by linking endothelial activation to endothelial injury.

Is Endothelial Activation a Critical Event in Thrombotic Thrombocytopenic Purpura?

Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy. The current pathophysiologic paradigm suggests that the ADAMTS13 deficiency leads to Ultra Large-Von Willebrand Factor multimers accumulation with generation of disseminated microthrombi. Nevertheless, the role of endothelial cells in this pathology remains an issue. In this review, we discuss the various clinical, in vitro and in vivo experimental data that support the important role of the endothelium in this pathology, suggesting that ADAMTS13 deficiency may be a necessary but not sufficient condition to induce TTP. The "second hit" model suggests that in TTP, in addition to ADAMTS13 deficiency, endogenous or exogenous factors induce endothelial activation affecting mainly microvascular cells. This leads to Weibel-Palade bodies degranulation, resulting in UL-VWF accumulation in microcirculation. This endothelial activation seems to be worsened by various amplification loops, such as the complement system, nucleosomes and free heme.

Macrophage IL-1ß-positive microvesicles exhibit thrombo-inflammatory properties and are detectable in patients with active juvenile idiopathic arthritis.

Objective: IL-1ß is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1ß-mediated disease such as systemic juvenile idiopathic arthritis (sJIA). Leukocyte microvesicles (MVs) may be a mechanism of IL-1ß secretion. The first objective of our study was to characterize IL-1ß-positive MVs obtained from macrophage cell culture supernatants and to investigate their biological functions in vitro and in vivo. The second objective was to detect circulating IL-1ß-positive MVs in JIA patients. Methods: MVs were purified by serial centrifugations from PBMCs, or THP-1 differentiated into macrophages, then stimulated with LPS ± ATP. MV content was analyzed for the presence of IL-1ß, NLRP3 inflammasome, caspase-1, P2X7 receptor, and tissue factor (TF) using ELISA, Western blot, or flow cytometry. MV biological properties were studied in vitro by measuring VCAM-1, ICAM-1, and E-selectin expression after HUVEC co-culture and factor-Xa generation test was realized. In vivo, MVs' ability to recruit leukocytes in a murine model of peritonitis was evaluated. Plasmatic IL-1ß-positive MVs were studied ex vivo in 10 active JIA patients using flow cytometry. Results: THP-1-derived macrophages stimulated with LPS and ATP released MVs, which contained NLRP3, caspase-1, and the 33-kDa precursor and 17-kDa mature forms of IL-1ß and bioactive TF. IL-1ß-positive MVs expressed P2X7 receptor and released soluble IL-1ß in response to ATP stimulation in vitro. In mice, MVs induced a leukocyte peritoneal infiltrate, which was reduced by treatment with the IL-1 receptor antagonist. Finally, IL-1ß-positive MVs were detectable in plasma from 10 active JIA patients. Conclusion: MVs shed from activated macrophages contain IL-1ß, NLRP3 inflammasome components, and TF, and constitute thrombo-inflammatory vectors that can be detected in the plasma from active JIA patients.

Pulmonary IgG4-related disease with favourable response to rituximab: A case report.

Pulmonary involvement of IgG4-associated disease is a rare condition with no codified treatment apart from steroid administration. We report here the case of a patient with pulmonary involvement of IgG4-RD successfully managed with Rituximab, in induction and maintenance therapy. This original case could support the use of Rituximab in rare situations of steroid-resistant or steroid-dependent pulmonary IgG4-RD.

Ocular Inflammation Induced by Immune Checkpoint Inhibitors.

Ocular immunotherapy-related adverse events (IRAEs), although rare, can be sight-threatening. Our objective was to analyze ocular IRAEs diagnosed in France from the marketing of immune checkpoint inhibitors (ICPIs) until June 2021 and to review the literature. We collected the cases of 28 patients (36 ocular IRAEs), occurring after an average of 17 weeks (±19). Forty-six percent of patients were treated for metastatic melanoma. Anti-PD1 agents were responsible for 57% of the IRAEs. Anterior uveitis was the most common (44%), followed by panuveitis (28%). Of 25 uveitis cases, 80% were bilateral and 60% were granulomatous. We found one case with complete Vogt-Koyanagi-Harada syndrome and one case of birdshot retinochoroidopathy. The other IRAEs were eight ocular surface disorders, one optic neuropathy, and one inflammatory orbitopathy. Seventy percent of the IRAEs were grade 3 according to the common terminology of AEs. ICPIs were discontinued in 60% of patients and 50% received local corticosteroids alone. The literature review included 230 uveitis cases, of which 7% were granulomatous. The distributions of ICPIs, cancer, and type of uveitis were similar to our cohort. Ocular IRAEs appeared to be easily controlled by local or systemic corticosteroids and did not require routine discontinuation of ICPIs. Further work is still warranted to define the optimal management of ocular IRAEs.

Thoracic involvement and imaging patterns in IgG4-related disease.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a rare orphan disease. Lung, pleura, pericardium, mediastinum, aorta and lymph node involvement has been reported with variable frequency and mostly in Asian studies. The objective of this study was to describe thoracic involvement assessed by high-resolution thoracic computed tomography (CT) in Caucasian patients with IgG4-RD. METHODS: Thoracic CT scans before treatment were retrospectively collected through the French case registry of IgG4-RD and a single tertiary referral centre. CT scans were reviewed by two experts in thoracic imagery blinded from clinical data. RESULTS: 48 IgG4-RD patients with thoracic involvement were analysed. All had American College of Rheumatology/European League Against Rheumatism classification scores ≥20 and comprehensive diagnostic criteria for IgG4-RD. CT scan findings showed heterogeneous lesions. Seven patterns were observed: peribronchovascular involvement (56%), lymph node enlargement (31%), nodular disease (25%), interstitial disease (25%), ground-glass opacities (10%), pleural disease (8%) and retromediastinal fibrosis (4%). In 37% of cases two or more patterns were associated. Asthma was significantly associated with peribronchovascular involvement (p=0.04). Among eight patients evaluated by CT scan before and after treatments, only two patients with interstitial disease displayed no improvement. CONCLUSION: Thoracic involvement of IgG4-RD is heterogeneous and likely underestimated. The main thoracic CT scan patterns are peribronchovascular thickening and thoracic lymph nodes.

Acute severe hepatitis in adult-onset Still's disease: case report and comprehensive review of a life-threatening manifestation.

Acute severe hepatitis is a rare complication of adult-onset Still's disease (AOSD). This condition is poorly characterized. We performed a review of the medical literature to describe clinical, biological, pathological, and treatment characteristics from AOSD patients with acute severe hepatitis. Their characteristics were compared with AOSD patients without severe hepatitis. Twenty-one cases were collected including a new case reported here. Patients with severe hepatitis were mostly young adults with a median age of 28 years (range: 20 to 55 years). Overall, patients with severe hepatitis had less arthritis, macular rash, sore throat, lymphadenopathy, or splenomegaly than patients without severe hepatitis. Cytopenia was more frequent in case of severe hepatitis. Most patients were treated with steroids, and the use of biotherapies has increased over the last decade. Despite treatment, 49% of patients required liver transplantation and 24% died. Key Points • Acute severe hepatitis in adult-onset Still's disease (AOSD) is associated with liver transplantation and/or death in, respectively, 43% and 24% of cases. • Severe hepatitis is the inaugural manifestation of AOSD in half of cases. Diagnosis is difficult when extra-hepatic clinical manifestations are lacking. • The mechanism of hepatic necrosis in AOSD with severe hepatitis is unknown. Liver biopsy is not specific and should not delay treatment initiation.

JAK inhibitors in 2019, synthetic review in 10 points.

JAK inhibitors are recent treatments. Many publications have appeared in recent years, exposing treatment efficiencies in phases 2 and 3 studies, or their tolerance profile in various rheumatological diseases. We propose here a systematic review of JAK inhibitors, from their mechanism of physiological action up to the estimation of their current risk benefit balance, and their possible future applications. In order to better synthesize the data, we organized this review into 10 essential points. 1- What is the role of JAK/Stat pathway? 2- How can a single signaling pathway regulate as many different signals? 3- What are the commercialized JAK inhibitors and their validated indications in humans today? 4- What is the level of efficiency of JAK inhibitors in inflammatory diseases? 5- What is the delay of efficiency of JAK inhibitors? 6- Where is the place of JAK inhibitors in the therapeutic strategy today? 7- What is the infectious tolerance profile of JAK inhibitors? 8- What is the non-infectious safety profile of JAK inhibitors? 9- What is the cost of JAK inhibitors compared to other DMARDs? 10- What future prospects for JAK inhibitors?